Down Syndrome (DS) is the major recognized cause of genetic mental retardation (MR) and affects the welfare of more than 300,000 individuals in the United States Alone. The brains of individuals with DS, although not grossly abnormal at birth, develop microcephaly with decreased size of the prefrontal cortex and cerebellar vermis, and show characteristic subtle abnormalities that include regression and distortion of the dendritic tree and spines, defective lamination of the cortex, and abnormal synapses. The ultimate goal of the research described in this proposal is to began to define the cause of these defects by elucidating the pathways between genes and cognition in Down syndrome and providing models in which to ameliorate them. In the past 5 years, a powerful arrays of tolls has been developed including chromosome 21 genes, the DS phenotypic map, and mouse models of DS. As a first step in identifying a subset of genes that are critical for the neuroanatomic and functional defects of DS, a consensus region for a part of DS mental retardation was generated by this component, and a dense contiguous array of clones covering more than 4 Mb of two critical regions was constructed, one homologous to MMU16 and the other to MMU10. We have isolated and characterized human and mouse gene homologs from these regions that are expressed in the human brain. These genes include DS-CAM, encoding a novel member of neural cell adhesion molecules, responsible for morphogenesis and function of the vertebrate brain. Expressed specifically in the nervous system, it occupies 10-15% of the entire candidate region, and it is a strong candidate for some subtle structural and cognitive defects of DS; PEP19, a peptide expressed only in the post-natal cerebellum and retina; CHD1, highly expressed in fetal brain and brown fat; hPWP2, a yeast homolog responsible for cell separation;TMEM, a large, ubiquitous transmembrane protein. We propose four aims: I. To characterize chromosome 21 gene expression in the brains of Down syndrome and controls during pre and post-natal development using Northerns, tissue in situ hybridization and immunocytochemistry. Genes will include DS-CAM, CHD1, hPWP2, PEP-19 and TMEM-1. II. To characterize mouse gene expression of human 21 homologues in normal, Ts65Dn and Cre-Lox mice with the appropriate duplications, using immunohistochemistry and tissue in situ hybridization. III. To construct transgenic and knockout mice using chromosome 21 genes expressed in the human brain. IV. To analyze transgenic and knockout mice in Aim III for general and neuroanatomy, gene expression and behavior. These models will provide clues to brain morphogenesis and cognition in DS and in normal developments as well as providing models in which to test strategies for treatment.